Cell cycle-dependent protein expression of mammalian homologs of yeast DNA double-strand break repair genes Rad51 and Rad52

Chen, Fanqing; Nastasi, Anthony; Shen, Zhiyuan; Brenneman, Mark A.; Crissman, Harry A.; Chen, David J.

doi:10.1016/s0921-8777(97)00020-7

Cited by 112 publications

(87 citation statements)

References 44 publications

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“…Propidium iodide sorting by fluorescence-activated cell sorting indicated that doxorubicin-treated SKLMS1 cells arrested in the S-G 2 -M cell cycle phase without concomitant increase in the apoptotic sub-G 1 fraction. Consistent with other studies showing a cell cycle phase -related expression of Rad51 (20), our findings indicate that Rad51 levels are highest in that phase of the cell cycle where doxorubicin exerts its principal effects. Because Rad51 overexpression per se stimulates Rad51 Suppression by siRNA Attenuates RD and SKLMS-1Doxorubicin Chemoresistance…”

Section: Rad51 Is Overexpressed In Sts Cell Lines In Vitro and In Vivosupporting

confidence: 92%

Rad51 overexpression contributes to chemoresistance in human soft tissue sarcoma cells: a role for p53/activator protein 2 transcriptional regulation

Hannay

Liu

Zhu

et al. 2007

Molecular Cancer Therapeutics

116

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We investigated whether Rad51 overexpression plays a role in soft tissue sarcoma (STS) chemoresistance as well as the regulatory mechanisms underlying its expression. The studies reported here show that Rad51 protein is overexpressed in a large panel of human STS specimens. Human STS cell lines showed increased Rad51 protein expression, as was also observed in nude rat STS xenografts. STS cells treated with doxorubicin exhibited up-regulation of Rad51 protein while arrested in the S-G 2 phase of the cell cycle. Treatment with anti-Rad51 small interfering RNA decreased Rad51 protein expression and increased chemosensitivity to doxorubicin. Because we previously showed that reintroduction of wild-type p53 (wtp53) into STS cells harboring a p53 mutation led to increased doxorubicin chemosensitivity, we hypothesized that p53 participates in regulating Rad51 expression in STS. Reintroduction of wtp53 into STS cell lines resulted in decreased Rad51 protein and mRNA expression. Using luciferase reporter assays, we showed that reconstitution of wtp53 function decreased Rad51 promoter activity. Deletion constructs identified a specific Rad51 promoter region containing a p53-responsive element but no p53 consensus binding site. Electrophoretic mobility shift assays verified activator protein 2 (AP2) binding to this region and increased AP2 binding to the promoter in the presence of wtp53. Mutating this AP2 binding site eliminated the wtp53 repressive effect. Furthermore, AP2 knockdown resulted in increased Rad51 expression. In light of the importance of Rad51 in modulating STS chemoresistance, these findings point to a potential novel strategy for molecular-based treatments that may be of relevance to patients burdened by STS. [Mol Cancer Ther 2007;6(5):1650 -60]

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Section: Rad51 Is Overexpressed In Sts Cell Lines In Vitro and In Vivosupporting

confidence: 92%

Rad51 overexpression contributes to chemoresistance in human soft tissue sarcoma cells: a role for p53/activator protein 2 transcriptional regulation

Hannay

Liu

Zhu

et al. 2007

Molecular Cancer Therapeutics

116

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“…Variations of Rad51 expression have been observed during cell cycle progression (Yamamoto et al, 1996;Chen et al, 1997) and during immortalization of primary human ®broblasts (Xia et al, 1997). In our hands, di erences in Rad51 protein levels in cancer cells are hardly detectable using antibody based methods.…”

mentioning

confidence: 57%

“…During cell cycle progression only minor variations in Rad51 protein level occur (Yamamoto et al, 1996;Chen et al, 1997). Immortalization of human ®bro-blasts is accompanied by a 3 ± 4-fold increase in Rad51 mRNA expression levels (Xia et al, 1997).…”

mentioning

confidence: 99%

DNA repair and recombination factor Rad51 is over-expressed in human pancreatic adenocarcinoma

et al. 2000

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Molecular processes that could contribute to di erences in chemo-and radioresistance include variations in DNA repair mechanisms. In mammalian cells, the product of the rad51 gene mediates DNA repair via homologous recombination. We describe that in contrast to conventional monolayer cell systems Rad51 protein accumulates to high-levels in three-dimensional cell culture models as well as in orthotopic xeno-transplants of human pancreatic cancer cells. Strikingly, over-expression of wild-type Rad51 was also found in 66% of human pancreatic adenocarcinoma tissue specimens. Functional analysis revealed that Rad51 over-expression enhances survival of cells after induction of DNA double strand breaks. These data suggest that perturbations of Rad51 expression contribute to the malignant phenotype of pancreatic cancer.

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“…First, the mammalian Rad51 protein is expressed late in the S and G2 phases, i.e. after the replication phase (Chen et al, 1997). Second, RAD51 similarly a ects mutagenesis and sister chromatid exchanges (SCE) which is a post-replication process: in the same cell lines used here, RAD51 has no e ect on spontaneous SCE whereas it a ects induced SCE (Lambert and Lopez, 2001).…”

Section: Effect Of Rad51status On Mutagenesismentioning

confidence: 99%

Inactivation of the RAD51 recombination pathway stimulates UV-induced mutagenesis in mammalian cells

Lambert

Lopez

2002

Oncogene

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We have examined the impact of the RAD51 recombination pathway on recombination and mutagenesis induced by UV-C in mammalian cells. We used hamster CHO cell lines that express di erent forms of Rad51 protein, resulting in stimulation or inhibition of spontaneous gene conversion. Spontaneous mutagenesis was a ected by none of the RAD51 forms. The wild-type mouse MmRAD51 a ects neither UV-induced recombination nor UV-induced mutagenesis. In contrast, the dominant negative SMRAD51 strongly impairs UV-induced recombination while it stimulates UV-induced mutagenesis. Our results show that a defect in the RAD51 gene conversion pathway reveals (a) mutagenic alternative pathway(s) to repair UV-damage, in mammalian cells.

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Cell cycle-dependent protein expression of mammalian homologs of yeast DNA double-strand break repair genes Rad51 and Rad52

Cited by 112 publications

References 44 publications

Rad51 overexpression contributes to chemoresistance in human soft tissue sarcoma cells: a role for p53/activator protein 2 transcriptional regulation

Rad51 overexpression contributes to chemoresistance in human soft tissue sarcoma cells: a role for p53/activator protein 2 transcriptional regulation

DNA repair and recombination factor Rad51 is over-expressed in human pancreatic adenocarcinoma

Inactivation of the RAD51 recombination pathway stimulates UV-induced mutagenesis in mammalian cells

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